The goal of this project is to develop a superior anti-nicotine vaccine for smoking cessation. A high incidence of smoking makes smoking-related diseases the leading cause of preventable death and morbidity. Even though 70% of smokers desire to quit and 40% of smokers attempt to stop smoking each year, less than 10% of these attempts are successful. Clearly, an urgent global need exists for more efficacious approaches to smoking cessation therapy. A promising approach is to vaccinate against nicotine, inducing nicotine specific antibodies to capture nicotine in the blood and inhibit passage to the brain, thus eliminating its addiction reinforcing activities. Supportive data from two independent phase II clinical trials indicate a correlation between anti-nicotine antibody titers and smoking cessation. However, in the published study, only one third of the study group achieved anti-nicotine titers sufficient to increase smoking cessation above placebo. Both trials used the conventional vaccine design strategy of linking the nicotine to a protein (a hapten-carrier approach). We postulate that a fundamentally new technological strategy to increase anti-nicotine titers is needed. Based on ground breaking targeted nanoparticle and immunology technologies from the laboratories of Robert Langer (MIT), Omid Farokhzad (Brigham &Women's Hospital and Harvard Medical School) and Ulrich von Andrian (Harvard Medical School), Selecta Biosciences has developed an entirely new approach to vaccine design to boost immune responses well beyond conventional technologies. Selecta's technology consists of synthetic immunomodulatory nanoparticles that home to antigen presenting cells (dendritic cells and B cells) to drive focused and highly prolific antigen-specific immune responses. The nanoparticles can be precisely engineered and comprise all of the key elements required to optimize an immune response: 1) Targeting to antigen presenting cells to enhance efficacy and reduce off target impact;2) B-cell antigen (nicotine) presentation at high surface density to stimulate rapid B-cell responses;3) T-cell antigen for T helper cell activation and the induction of efficient immune memory;4) Adjuvant (Toll-like receptor agonist) for cell specific immune activation, and 5) Biocompatible polymers for the time release of active components. The nanoparticles are produced in a proprietary, scalable, one-step self-assembly process from synthetic building blocks. Selecta's prototype nicotine vaccine nanoparticle has induced significant nicotine serum-antibody levels in mice. This work will serve as a basis for optimization efforts to achieve antibody titers well in excess of conventional vaccine technologies. Our ultimate goal in this proposed project is to complete the preclinical development of a superior smoking cessation therapeutic vaccine ready for IND submission followed by a phase 1 clinical trial. The project will focus on four specific aims: 1) to optimize the nanoparticle;2) to complete CMC development activities;3) to complete GLP toxicology studies suitable to support filing of an IND;4) to complete phase I human clinical safety testing. PUBLIC HEALTH RELEVANCE: Selecta Biosciences, Inc. is applying advances in immunology and nanoparticle technology to develop a novel class of vaccines based on nanoparticle technology which will induce high levels of circulating antibodies against nicotine in smokers who desire to quit. The induced antibodies promote smoking cessation by binding to nicotine in the blood and preventing it from crossing the blood brain barrier and thus preventing the addictive effects of nicotine in the brain. This project seeks support to develop the nanoparticle vaccine through an initial Phase 1 clinical trial in people.